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Hepatocellular Carcinoma
Renown
Univ Nevada Reno
Dept of Medicine: Teaching Conf
May 2009
Disclosures: that are relevant to this presentation I have consulting and speaker arrangements with
– Bayer
– Onyx
I have research contract relationships with
– BMS
– Bayer/Onyx
I do not own stock or have any investment positions in any company relative to this presentation
HCC: Epidemiology
HCC is the most common primary liver malignancy
Worldwide incidence >600,000 cases per year
– Liver cancer is the most rapidly increasing cancer in the U.S.
– 19,160 new cases and 16,780 deaths in 2007
More common in men than women (4:1)
For resection, rate of recurrence can be as high as 50% at 2 years
– Only 12% are eligible for resection or for transplant
– 80%-90% of HCC cases occur in cirrhotic livers
International Agency for Cancer Research. Globocan 2002. Available at: http://www-dep.iarc.fr. Accessed February 19, 2008; Parkin DM et al. Int J Cancer. 2001;94;153-156; American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA; American Cancer Society, 2007. McGlynn KA et al. Int J Cancer. 2001;94:290-296; McGlynn KA et al. Cancer Epidemiol Biomarkers Prev. 2006;15:1198-1203; Jemal A et al. CA Cancer J Clin. 2006;56:106-130; El-Serag HB. Gastroenterology. 2004;127:S27-S34.
Burden of HCC in the United States
Annual prevalence, incidence, and survival with HCC estimated from SEER database
Costs distribution of costs estimated from 392 HCC patients
Annual estimated cost of HCC in the United States: $454.5 million
– Per-patient cost: $32,907
Healthcare costs accounted for 89.2% of cost
Lost productivity accounted for 10.8% of cost
Lang K, et al. J Hepatol. 2008. In press.
Goodman Z.
Goodman Z.
HCC incidenceHCC incidencetripled over the last three decadestripled over the last three decades
Altekruse, JCO 2009Altekruse, JCO 2009
White Black Hispanic Asian Other Unknown
HC
C (
%)
Kim WR, et al. AASLD 2002. Abstract 223.
25
147
51
04
0
20
40
60
80
100
Proportion of HCC by Patient Race Among Hospitalizations for HBV (1998)
Racial Differences in Survival of Patients with HCC
Racial Differences in Survival of Patients with HCC
CaucasianCaucasian
BlackBlackAsianAsian
HispanicHispanic
00
YearsYears
Su
rviv
al (
%)
Su
rviv
al (
%)
2020
4040
6060
8080
100100
00 11 22 33
Davila J, El-Serag HB. Clin Gastro Hepatol; 2006Davila J, El-Serag HB. Clin Gastro Hepatol; 2006
HCC PrognosisHCC Prognosis
Survival has been improving over last 15 yearsSurvival has been improving over last 15 years Improved survival after resectionImproved survival after resection More diagnosis at earlier stage (screening!)More diagnosis at earlier stage (screening!) More local therapy availableMore local therapy available
0%10%20%30%40%50%
'92-'93 '94-'96 '97-'99 '00-'02 '03-'05
1 Year Survival of HCC
Altekruse, JCO 2009Altekruse, JCO 2009
Overview Screening and Surveillance for HCC: who is at risk and how/when to
screen and complete follow up surveillance
Biomarkers
Imaging
Pathology
Liver Transplant
Regional Therapy for HCC
– Medical Management of Patients Undergoing Regional Therapy for Hepatocellular Carcinoma
Current Trends in the Treatment of Patients With Advanced HCC
Systemic Therapy and Supportive Care in Patients With Advanced Hepatocellular Carcinoma
Management of Hepatocellular Management of Hepatocellular Carcinoma Requires a Carcinoma Requires a
Multidisciplinary ApproachMultidisciplinary Approach
Radiation OncologyRadiation Oncology
PathologyPathology
OncologyOncology
RadiologyRadiology
Hepatobiliary Surgery
Hepatobiliary Surgery
HepatologyHepatology
13
Risk Factors for HCC in US Patients Obesity
Polesel J, et al. Ann Oncol. 2008;[Epub ahead of print]. BFRSS Database. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed October 21, 2008.Polesel J, et al. Ann Oncol. 2008;[Epub ahead of print]. BFRSS Database. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed October 21, 2008.
Emerging Risk Factor: Obesity (BMI ≥ 30)Emerging Risk Factor: Obesity (BMI ≥ 30)
No Data
< 10% 10-14% 15-19% 20-24% 25-29% ≥ 30%
Background
In the United States and Europe, the majority of HCC develops in the setting of underlying liver cirrhosis
Treatment strategies for HCC should avoid worsening liver function to such an extent that would offset their possible benefit
Staging systems for treatment allocation, therefore, must concurrently consider tumor extension and severity of the underlying liver function impairment
There is no universally accepted staging system for HCC
The BCLC staging system for HCC is the most widely used in Western countries, particularly for treatment allocation
Malignant TransformationMultistep
Potential Targets
Oxidative stress and inflammation
Viral oncogenes Carcinogens
Growth factors Telomere shortening
Cancer stem cells
Loss of cell cycle checkpoints
Antiapoptosis Angiogenesis
Normal liver
Liver cirrhosis
Hepatitis CHepatitis B
EthanolNASH
Epigenetic alterationsGenetic alterations
HCC[2]
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.
•Event a 3rd line treatment such as lamivudine can decrease HCC risk
•After El Serag EASL 2007
Screening and surveillance for HCC is the standard of care
SOC
•Screening: first test
•Surveillance: all subsequent testing – typically on a regular schedule
AASLD Practice Guidelines on Screening & Surveillance for HCC AASLD recommends surveillance using AFP + US every 6-12 months for at-
risk patient groups:
– Hepatitis B carriers
– Asian males >40 years
– Asian females >50 years
– All cirrhotic hepatitis B carriers
– Family history of HCC
– Africans >20 years
– Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past levels of inflammatory activity
– Cirrhosis due to hepatitis C, alcohol, or other causes
Bruix & Sherman. AASLD Practice Guideline: Management of Hepatocellular Carcinoma, Hepatology 2005; 42(5): 1208.
HCC Screening by Ultrasound
Performance characteristics of ultrasound as a screening test
Performance Characteristic, %
Cohort 1Years 1-5
Cohort 1Years 6-8
Cohort 2Years 1-3
Sensitivity 79 87 80
Specificity 94 87 91
PPV 15 13 14
NPV 98 100 100
Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file.
Surveillance for HCC Reduces Surveillance for HCC Reduces Mortality:Mortality:
A Randomized Controlled TrialA Randomized Controlled Trial
Zhang BH, et al. J Cancer Res Clin Oncol 2004Zhang BH, et al. J Cancer Res Clin Oncol 2004
00
Time (Years) Time (Years)
11 22 33 44 5500
.8.8
.6.6
.2.2
.4.4
ScreeningScreening
Su
rviv
al P
rob
abil
ity
(%)
Su
rviv
al P
rob
abil
ity
(%)
ControlControl
Screening/surveillance Current Strategies: US and AFP
US q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S.
Rationale for 6-month screening/surveillance interval
– Doubling time: median = 6 mo (range, 1-19 mo)
– Growth from 1 to 3 cm: 4 mo for most aggressive, 18 mo for moderately aggressive, 5 yr for indolent HCC
Median detectable subclinical period for HCC = 3.2 yr
Making the diagnosis of HCC
Biopsy is very rarely indicated
– Risk of tracking tumor cells
– High false negative rate
Diagnosis is by imaging criteria
DIAGNOSTIC CRITERIA FOR HCC
EASL CONFERENCES ON HCC, BARCELONA 2005AASLD PRACTICE GUIDELINE, HEPATOLOGY 2005
• Cyto-histological criteria
• Non-invasive criteria (cirrhotic patients)
1. One imaging technique * Focal lesion > 2 cm with arterial hypervascularizationand venous wash-out
2. Two coincident imaging techniques * Focal lesion 1-2 cm with arterial hypervascularizationand venous wash-out
* Three techniques considered: contrast US, CT, and dynamic MRI
AP
PVP
Arterial Phase hypervascular necrotic
Portal Venous Phase“washout” to less than liver
HCC
How do we use AFP ?
AFP is a useful biomarker of a patients increased RISK for HCC in the future
AFP is not a screening or surveillance tool for HCC
Performance Characteristics ofAFP to diagnose HCC Based on Cutoff Level
Colli A, et al. Am J Gastro 2005
Cutoff 10-11 17-21 50 > 100Studies 4 7 4 5(#)
%
Sensitivity/Specificity of DCP and AFP as a Function of Disease Stage Effect of tumor size on the diagnosis of HCC by DCP, AFP
Nakamura S, et al. Am J Gastroenterol. 2006;101:2038-2043.
DCP
Tumor Size Tumor Size
AFP
1-Specificity
Sen
siti
vity
0
0.2
0.4
0.6
0.8
1.0
0 0.2 0.4 0.6 0.8 1.0
3 cm3-5 cm5 cm
1-Specificity
Sen
siti
vity
0
0.2
0.4
0.6
0.8
1.0
0 0.2 0.4 0.6 0.8 1.0
3 cm3-5 cm5 cm
AMERICAN JOURNAL OF GASTROENTEROLOGY by Nakamura S, et al. Copyright 2006 by Blackwell Publishing - Journals. Reproduced with permission of Blackwell Publishing - Journals in the format Copy via Copyright Clearance Center.
Months
AF
P: n
g/m
L
AF
P-L
3%
AFP conc. AFP-L3 conc. AFP-L3%
AFP L3% rises before AFP in typical course of HCC occurrence case
21 months
HCC diagnosisTumor size:
3-5 cm
Before HCC diagnosis
Tumor size: ≤ 2 cm
Sterling, Am J Gastro
Current Biomarkers and Risk of Portal Vein Invasion AFP-L3 ≥ 15%
– RR: 2.459 (95% CI: 1.005-6.017; P = .0487)
DCP ≥ 100 mAU/mL
– RR: 3.019 (95% CI: 1.077-8.464; P = .0357)
Number of HCC tumors ≥ 2
– RR: 4.912 (95% CI: 1.619-14.905; P = .0049)
Hagiwara S, et al. J Gastroenterol. 2006;41:1214-1219.
Current Biomarkers and Risk of Microvascular Invasion Independent predictors of microvascular invasion
– Tumor size (< 2, 2-4, > 4 cm)
– Odds ratio: 3.4 (95% CI: 1.5-4.1)
– Preoperative DCP levels (< 100, 100-500, > 500 mAU/mL)
– Odds ratio: 2.2 (95% CI: 1.1-2.4)
– Tumor grade (3-grade system)
– Odds ratio: 2.2 (95% CI: 1.1-3.7)
Shirabe K, et al. J Surg Oncol. 2007;95:235-240.
Incidence of Portal Venous Invasion of HCCin relation to the Serum DCP level at diagnosis
DCP(-): 183 patients with DCP < 100 mAU/mL
Koike Y, et al. Cancer 2001 Feb 1;91(3):561-9
DCP(+): 37 patients with DCP > 100 mAU/mL
DCP predicts clinical course
HCC: overall survival
HCC is treatable
HCC is curable !–In selected patients–Justifying screening and surveillance
Management of HCC
Liver transplantation
Resection
Tumor ablation
– Radiofrequency thermal ablation
– Alcohol injection
– Chemoembolization
Targeted molecular therapy
Chemotherapy
– Regional/systemic
Potentially curative
Staging Strategy and Treatment for Patients With HCC
Liver transplant PEI/RF
Curative treatments
TACE
HCC
Single
Increased Associateddiseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion, N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules ≤ 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
≤ 3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic (unless LT)
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.
Treatment for HCC Often Suboptimal
Proportion of patients receiving potentially curative therapy
– 34.0% of patients with single lesions
– 34.0% of patients with lesions < 3 cm
– 19.3% of patients with lesions > 10 cm
– 4.9% of patients with metastatic disease
11.5% of patients ideal for transplantation received it
14.3% of patients ideal for surgical resection received it
El-Serag HB, et al. J Hepatol. 2006;44:158-166.
0.0040.0040.0040.0041.46-7.191.46-7.191.46-7.191.46-7.193.243.243.243.24 AtlantaAtlanta AtlantaAtlanta
0.0100.0100.0100.0101.29-6.291.29-6.291.29-6.291.29-6.292.852.852.852.85 New MexicoNew Mexico New MexicoNew Mexico0.0070.0070.0070.0071.28-4.741.28-4.741.28-4.741.28-4.742.472.472.472.47 Los AngelesLos Angeles Los AngelesLos Angeles0.0470.0470.0470.0471.01-4.551.01-4.551.01-4.551.01-4.552.152.152.152.15 IowaIowa IowaIowa
0.2870.2870.2870.2870.73-3.000.73-3.000.73-3.000.73-3.001.471.471.471.47 San FranciscoSan Francisco San FranciscoSan Francisco
0.5650.5650.5650.5650.60-2.590.60-2.590.60-2.590.60-2.591.241.241.241.24 SeattleSeattle SeattleSeattle
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Geographic Variations in Receipt of Potentially Curative Therapy in the Elderly
Adjusting for time period, age, sex, comorbidity,liver disease severity, tumor size, risk factors for HCC
Geographic Variations in Receipt of Potentially Curative Therapy in the Elderly
Adjusting for time period, age, sex, comorbidity,liver disease severity, tumor size, risk factors for HCC
Influence of Cirrhosis on Operative Mortality for HCC
StudyMortality of
Non-cirrhoticsMortality of Cirrhotics
Shanghai 2nd Mil Col, 1960-1977
2% 12%
Keio Univ, 1973-1988 3% 13%Chang Gung Mem Hosp,
1977-19872% 7%
Med Hochschule Hannover, 1974-1988
7% 23%
Shimane Univ, 1980-1990 6% 12%
Hopital Paul Brousse, 1980-1991
3% 10%
MSKCC, 1970-1992 1% 14%
Surgical Resection: only for patients without portal hypertension
Hepatic resection
Percentage of HCCs deemed resectable at diagnosis
1
2
30% resectable
70% unresectable
Colombo, Antiviral Research, 2003
Treatment of HCC in US non-Federal Hospitals in 2000
Surgical Resection: 4.9%
Liver Transplant: 1.8%
Local Ablation: 3.5%
Embolization: 5.5%
Chemotherapy: 11%
Kim WR et al. Gastroenterology 2005
Su
rviv
alS
urv
ival
00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55
Follow up Duration (Years) Follow up Duration (Years)
TransplantTransplant
ResectionResection
AblationAblationTACETACE
11
0.80.8
0.60.6
0.40.4
0.20.2
00
Outcomes of HCC Treatment in the Elderly
El-Serag HB et al J Hepatology 2006
Ablation
RFA or TACE is/are the current standard(s)
PEI is for developing countries with limited resources
Microwave is faster to full tumor ablation but resources are expensive
Cryosurgery is no longer used due to length of time of procedure and complications of “ice ball”
-Survival Rates of Patients with small HCC treated with RFA
Trial Year Type of study
# of Pts
Survival Rate %
1 yr 3 yr 5 y
Recurrence Rate %
1y 3 y 5 y
Lencioni
et al
1997 Prospective 206 97 71 48 18 55 83
Lencioni
et al
2000 RCT 102 100 98
Rossi et al 2000 Prospective 41 87 50 19 47
Guglielmi et al
2000 Prospective 53 87 45
Siperstein 2000 Prospective 548 77 38
Cervantes 2003 Prospective 34 94 61 0 20
Treatment: Chemoembolization
Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery
Tumor receives most of its blood supply from the hepatic artery
Injection into the hepatic artery spares most of the normal liver
Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor
Tumor
Liver
Portal vein
Hepaticartery
Catheter placement forchemoembolization
TACE vs Surgical Resection: A Case-Control Prospective Study
TechniqueSurvival, %
Year 1 Year 2 Year 3 Year 5
TACE 96 80 56 30
Surgical resection 90 80 70 52
N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm
Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0– BUT for tumors > 3 cm and/or CLIP stage 1-2, 5-year survival identical for
both groups (27%)
Median OS (P = .1529)– Resection: 65.1 months– TACE: 50.4 months
Lee HS, et al. J Clin Oncol. 2002;20:4459-4465.
Chemoembolization: Efficacy Before Transplantation Major issue: dropout rate (~ 20%)
– Lower in US since adoption of MELD criteria
Role of TACE
– Control tumor and prevent progression
– Should be considered if waiting time > 6 months
Complications from TACE: rare (no increased rate of hepatic artery complications)
Richard HM 3rd, et al. Radiology. 2000;214:775-779.Graziadei IW, et al. Liver Transpl. 2003;9:557-563.Alba E, et al. Am J Roentgenol. 2008;190:1341-1348.
Primary Treatment Modality Used in Korea
TACE 48.2%
RFA1.5%
Surgery 11.2%
Chemotherapy7.5%
Radiotherapy2.1%
Conservative treatment 29.5%
N = 1078
Joong-Won Park, MD, National Cancer Center. Adapted with permission.
Chemoembolization: Randomized Trials (Nearly Identical Techniques)
TechniqueSurvival, %
Year 1 Year 2 Year 3
TACE 57 31 26
Supportive care 32 11 3
TechniqueSurvival, %
Year 1 Year 2
TACE 82 63
Supportive care 63 27
Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal)
Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
New Therapies Under New Therapies Under InvestigationInvestigation
Targeted and Targeted and ChemotherapyChemotherapy
Sorafenib* (Nexavar)Sorafenib* (Nexavar) Erlotinib (Tarceva)Erlotinib (Tarceva) Sirolimus (Rapamune)Sirolimus (Rapamune) Capecitabine (Xeloda)Capecitabine (Xeloda) Floxuridine (FUDR)Floxuridine (FUDR) Bevacizumab Bevacizumab
(Avastin)(Avastin) Sargramostim Sargramostim
(Leukine)(Leukine) Oxaliplatin (Eloxatin)Oxaliplatin (Eloxatin) Imatinib (Gleevac)Imatinib (Gleevac)
Local TherapyLocal Therapy Radiation TherapyRadiation Therapy
9090Yttrium microspheres Yttrium microspheres (Therasphere/SIRsphere)(Therasphere/SIRsphere)
Stereotactic RadioSurgery Stereotactic RadioSurgery (Cyberknife)(Cyberknife)
Doxorubicin Doxorubicin Eluting Beads (DC Eluting Beads (DC Bead)Bead)
Photoactive Photoactive chemicals (Litx)chemicals (Litx)
* Sorafenib approved November * Sorafenib approved November 20072007
Absolute contraindications
– Child-Pugh class C disease
– Poor performance status (ECOG PS > 2)
Relative contraindication
– Extrahepatic disease (benefit unclear)
Former contraindication
– PVT
– Minimize embolization and be more selective
Chemoembolization: Ineligibility Criteria
Chemoembolization: Predictors of Survival Lo et al[1]
– Absence of presenting symptoms (ECOG PS < 2)
– Absence of portal vein obstruction
– Tumor size (≤ vs > 5 cm)
– Okuda stage (I vs II)
Llovet et al[2]
– Absence of constitutional syndrome (ECOG PS < 2)
– Low serum bilirubin
– Treatment response (modified WHO criteria, > 6 months)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors
Yttrium-90 microspheres
– Average diameter: 20-30 µm
– 100% pure beta emitter (0.9367 MeV)
– Physical half-life: 64.2 hours
– Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm)
Intra-arterial Radioembolization With Yttrium-90: Rationale and History
Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.
Clinical Response to Yttrium-90 MicrospheresOutcome Dancey
et al[1]
(N = 20)
Carr et al[2]
(N = 65)Geschwind
et al[3]
(N = 80)
Salem et al[4]
(N = 43)
Response rate, % 39 47
Median survival 378 days(> 104 Gy)
Okuda stage I 649 days 628 days 24.4 mos
Okuda stage II 302 days 384 days 12.5 mos
1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681.2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110.3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205.4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.
Drug Eluting Beads
LC Bead is a Drug Delivery Embolisation System capable of loading and the controlled release of high doses of chemotherapeutic agents
– Doses per ml and per treatment:
– Doxorubicin maximum dose of 37.5mg/ml and 150mg/treatment with 4ml
Novel N-fil technology sulphonate modified hydrogel polymer
Blue tinted to aid visualisation
Delivered as vials containing 2ml Beads in 6ml saline
LC Bead is available in 3 sizes.
– 100-300um
– 300-500um
– 500-700um
Mechanism of Loading the LC Bead with Doxorubicin
The LC Bead has a negative charge where as doxorubicin has a positive charge…
The doxorubicin is loaded and eluted by an ‘reversible ionic exchange mechanism’.
Hydrated Beads
Hydration shell associated with PVA and ionic groups
Bulk (non-bound) waterInteraction of doxorubicin with SO3 groups displaces water from the hydration shells
Loaded Beads
Reducing Systemic Exposure
This is the relative drug distribution for standard arterial chemotherapy vs. conventional TACE vs. precision TACE
Relative Drug Distributions
Conventional TACE vs DCBs-TACEOverall 6-Month Tumour Response Rates
p = 0.11
Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response
Lammer et al, CIRSE 2008
ComplicationsSAE Comparison : Conventional TACE vs PRECISION TACE
75% Reduction in SAE’s at the same institution
90Yttrium vs. TACE
90Yttrium does not occlude the vessels at the arteriolar level
– Option for repeat embolic treatment
– Less ischemic damage
Response rates seem to be similar (no head-to-head comparisons)
Equivalent side effect profile
90Yttrium can be used in portal vein thrombosis and in more extensive disease
TACE accepted as treatment of choice for unresectable (nonablatable?) HCC
Prolonged survival established through randomized trials and prospective studies
Best vs good performance status, Child-Pugh class A-B
Role for yttrium-90 microspheres
Growing role for doxorubicin-loaded beads, pending outcome of clinical trials
Conclusions
Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and
2% to 5% of recurrent HCC
Staging Strategy and Treatment for Patients With HCC
Liver transplant PEI/RF TACE
HCC
Single
Increased Associateddiseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion, N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules ≤ 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
≤ 3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic (unless LT)Nonsurgical treatments: applicable
overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of
recurrent HCC
Liver Transplantation
The only treatment with a major chance of cure for HCC
Su
rviv
alS
urv
ival
00 0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55
Follow up Duration (Years) Follow up Duration (Years)
TransplantTransplant
ResectionResection
AblationAblationTACETACE
11
0.80.8
0.60.6
0.40.4
0.20.2
00
Outcomes of HCC Treatment in the Elderly
El-Serag HB et al J Hepatology 2006
Liver Transplant for HCC in cirrhosisMilan Criteria (Stage I+II)
++Absence of Macroscopic Vascular Invasion
Absence of Extrahepatic Spread
Single, not > 5cm Up to 3, none > 3cm
Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.
0.2
0.4
0.6
1
0 12 24 36 48 60Time (months)
Su
rviv
al
Transplant N=239
Other Treatment N=917
Survival Curves for Transplant vs. Other Treatment for Hepatocellular Carcinoma
0.8
Automatic MELD Upgrades for patients with unresectable HCC
Surgery with resection is the current standard of care for patient without cirrhosis
22 points at diagnosis
25 points 3 months
28 - 6 months
29 - 9 months
31 – 12 months
Liver Transplantation For HCC in patients with cirrhosis
Four -Year Survival
0
10
20
30
40
50
60
70
80
Unselected 1991 Milan Criteria Other Dx
40%
75% 76%
%Surviving
Mazzaferro N Engl J Med 1996
Intermediate/Advanced HCC: Future Directions 499 trials registered at clinicaltrials.gov for HCC as of
August 21, 2008, including
– Improving efficacy of RF and TACE (drug-eluting beads)
– Exploring alternative treatments for intermediate HCC (yttrium-90)
– Molecularly targeted agents in combination regimens (advanced HCC)
– Molecularly targeted agents in combination with current modalities (early/intermediate HCC)
– Improving tumor targeting of chemotherapeutic agents
– New molecular targets and new molecularly targeted agents
Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and
2% to 5% of recurrent HCC
Staging Strategy and Treatment for Patients With HCC
Liver transplant PEI/RF TACE
HCC
Single
Increased Associateddiseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion, N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules ≤ 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
≤ 3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic (unless LT)Nonsurgical treatments: applicable
overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of
recurrent HCC
Evidence of Benefit in Treatment of HCC (cont’d)Treatment Benefit Evidence
Systemic therapies
Sorafenib Increased survivalRandomized trial, meta-analysis, double blinded
Tamoxifen No benefitRandomized trial, meta-analysis, double blinded
Chemotherapy No benefitRandomized trial, meta-
analysis, nonblinded
IFN No benefitRandomized trial, meta-
analysis, nonblinded
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Key Pathways in Hepatocarcinogenesis: Possible Targets for Novel Therapies Growth factor-stimulated receptor tyrosine kinase signaling
Wnt/beta-catenin pathway
p13Kinase/AKT/mTOR
JAK/STAT signaling
Angiogenic signaling pathways
p53 and cell cycle regulatory pathways
Ubiquitin-proteasome pathway
Epigenetic promoter methylation and histone acetylation pathways
Ras-Raf-MEK-MAPK pathway
Roberts LR, et al. Semin Liver Dis. 2005;25:212-225.
OS in the SHARP and Asia-Pacific Trials
Months from Randomization
Su
rviv
al P
rob
abil
ity
Sorafenib (n=299)Median: 10.7 months95% CI: 9.4-13.3
Placebo (n=303)Median: 7.9 months95% CI: 6.8-9.1
HR (S/P): 0.6995% CI: 0.55-0.87P=0.00058
0.25
0.50
0.75
1.00
00
4 8 12 16 20
SHARP1
Sorafenib (n=150)Median: 6.5 months 95% CI: 5.6-7.6
Placebo (n=76)Median: 4.2 months 95% CI: 3.7-5.5
HR (S/P): 0.68 95% CI: 0.50-0.93P=0.014
0.25
0.50
0.75
1.00
00
4 8 12 16 20
Asia-Pacific2
Months from Randomization
Su
rviv
al P
rob
abil
ity
1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390.2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. © 2008, Massachusetts Medical Society. All rights reserved.
AEs, % Sorafenib (N = 297) Placebo (N = 302) P Value
Any Grade
Grade 3 Grade 4 Any Grade
Grade 3 Grade 4
Any Grade
Grade 3 or 4
Overall incidence 80 52
Constitutional symptoms
Fatigue 22 3 1 16 3 < 1 .07 1.00
Weight Loss 9 2 0 1 0 0 < .001 .03
Dermatologic events
Alopecia 14 0 0 2 0 0 < .001 NA
Dry skin 8 0 0 4 0 0 .04 NA
Hand-foot skin reaction
21 8 0 3 < 1 0 < .001 < .001
Pruritus 8 0 0 7 < 1 0 .65 1.00
Rash or desquamation
16 1 0 11 0 0 .12 .12
Other 5 1 0 1 0 0 < .001 .12
The SHARP Trial: Drug-Related AEs
Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.
Hand-Foot Syndrome
Strategies for Managing AEs
Hand-foot syndrome
– Creams and lotions
– Avoid tight footwear
– May require dose reduction
Diarrhea
– Antidiarrheal agents if severe
Fatigue
– Consider modafinil or methylphenidate if severe
Hypertension
– Start or adjust antihypertensives
Possible Future Studies in HCC
New targeted molecular agents
Small molecules in combination
– With each other
– With local ablation
– With conventional chemotherapy
Summary
Hepatocellular Carcinoma
– Prevention is possible by vaccine
– Risk driven by cirrhosis
– Viral load in HBV
– Treatment of underlying disease decreases risk
– Surveillance for HCC is SOC in selected patients
– HCC is curable in some patients
– Team approach is current standard to manage HCC
Management of Hepatocellular Management of Hepatocellular Carcinoma Requires a Carcinoma Requires a
Multidisciplinary ApproachMultidisciplinary Approach
Radiation OncologyRadiation Oncology
PathologyPathology
OncologyOncology
RadiologyRadiology
Hepatobiliary Surgery
Hepatobiliary Surgery
HepatologyHepatology